Microvascular permeability to macromolecules in human melanoma xenografts assessed by contrast-enhanced MRI - intertumor and intratumor heterogeneity

Several novel macromolecular anticancer agents have fallen short of expecta tions owing to inadequate and heterogeneous uptake in tumor tissue. In the present work, contrast-enhanced magnetic resonance imaging was used to meas ure the intertumor and intratumor heterogeneity in the effective microvascu lar permeability constant, P-eff, of an 82 kDa macromolecule in an attempt to identify possible causes of the inadequate and heterogeneous uptake. Tum ors of two human melanoma xenograft lines (A-07 and R-18) were included in the study. Human serum albumin with 30 gadopentetate dimeglumine units per molecule was used as a model molecule of macromolecular therapeutic agents. P-eff was measured in manually defined regions of interest, corresponding to a whole tumor (ROIWHOLE) or to subregions of a tumor (ROIs(SUB)). The P- eff of the ROIWHOLE Of individual tumors ranged from 1.4 x 10(-7) cm/s to 2 .8 x 10(-7) cm/s (A-07) and from 7.7 x 10(-8) cm/s to 3.2 x 10(-7) cm/s (R- 18). P-eff decreased with increasing tumor volume in R-18, but was independ ent of tumor volume in A-07. The intratumor heterogeneity in P-eff exceeded the intertumor heterogeneity in both tumor lines. Some ROIs(SUB) showed P- eff values that were similar to or slightly higher than the P-eff values of albumin in normal tissues. Our observations suggest that inadequate and he terogeneous uptake of macromolecular therapeutic agents in tumor tissue is partly a result of low and heterogeneous microvascular permeability. Howeve r, the microvascular wall is probably not the major transport barrier to ma cromolecules in A-07 and R-18 tumors, as most individual tumors and individ ual tumor subregions showed high P-eff values, i.e. values that are up to 1 0-fold higher than those of normal tissues. (C) 2001 Elsevier Science Inc. All rights reserved.